Prognosis Factors in Probands with an FBN1 Mutation Diagnosed Before the Age of 1 Year

Prognosis Factors in Probands With an FBN1 Mutation Diagnosed Before the Age of 1 Year

CHANTAL STHENEUR, LAURENCE FAIVRE, GWENAE¨ LLE COLLOD-BE´ ROUD, ELODIE GAUTIER, CHRISTINE BINQUET, CLAIRE BONITHON-KOPP, MIREILLE CLAUSTRES, ANNE H. CHILD, ELOISA ARBUSTINI, LESLEY C. ADE` S, UTA FRANCKE, KARIN MAYER, MINE ARSLAN-KIRCHNER, ANNE DE PAEPE, BERTRAND CHEVALLIER, DAMIEN BONNET, GUILLAUME JONDEAU, AND CATHERINE BOILEAU Service de Pe´diatrie [C.S., B.C.], Hoˆpital Ambroise Pare´, Boulogne, 92100 France; Consultation multidisciplinaire Marfan [G.J.], Hoˆpital Bichat, Paris, 75018 France; Centre de Ge´ne´tique [L.F.], CHUDijon, Dijon, 21000 France; Centre d’Investigation Clinique– Epide´miologie-Clinique/essais cliniques [L.F., E.G., C.B., C.B.-K.], CHU Dijon, Dijon, 21000 France; INSERM, U827 [G.C.-B., M.C.], Universite´ Montpellier, Montpellier, 34000 France; Department of Cardiological Sciences [A.H.C.], St Georges Hospital, London SW17 0RE, United Kingdom; Molecular Diagnostic Division [E.A.], IRCCS Foundation San Matteo Hospital, Pavia, 27100 Italy; Marfan Research Group and Department of Clinical Genetics [L.C.A.], Children’s Hospital at Westmead, New South Wales 2145, Australia; Department of Genetics and Pediatrics [U.F.], Stanford University Medical Center, Stanford, California 94305; Center for Human Genetics and Laboratory Medicine [K.M.], Martinsried, 82152 Germany; Institut fu¨r Humangenetik [M.A.-K.], Hannover Medical School, Hannover, 30625 Germany; Center for Medical Genetics [A.D.P.], Ghent University Hospital, Ghent, 9000 Belgium; Service de Cardiologie Pediatrique [D.B.], Hoˆpital Necker-Enfants-Malades, Paris, 75015 France

ABSTRACT: Marfan syndrome (MFS) is an autosomal dominant along the entire FBN1 gene. MFS is notable for its variability connective tissue disorder. Diagnostic criteria of neonatal MFS in age of onset, tissue distribution, and severity of clinical (nMFS), the most severe form, are still debated. The aim of our study manifestations. neonatal Marfan syndrome (nMFS) is consid- was to search for clinical and molecular prognostic factors that could ered the most severe end of the spectrum of type I fibrilli- be associated with length of survival. Probands ascertained via the nopathies, but diagnostic criteria are still debated. Indeed, framework of the Universal Marfan database-FBN1, diagnosed be- Booms et al. (4) proposed to reserve the term of nMFS for fore the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. patients diagnosed at birth or within the first 3 mo of life, Clinical and molecular data were correlated to survival. Among the presenting with pronounced atrioventricular valve dysfunc- 60 individuals, 38 had died, 82% died before the age of 1 y, mostly tion, with death often occurring within the first year of life because of congestive heart failure. Three probands reached adult- because of congestive heart failure. Pulmonary emphysema, hood. Valvular insufficiencies and diaphragmatic hernia were predic- joint contractures, crumpled ears, and loose skin are often tive of shorter life expectancy. Two FBN1 mutations were found associated. They also suggested, like others, that all mutations outside of the exon 24–32 region (in exons 4 and 21). Mutations in causing nMFS cluster in a specific region between exons 24 exons 25–26 were overrepresented and were associated with shorter and 32 (4–6). According to the most recent comment on the ϭ survival (p 0.03). We report the largest genotyped series of subject by Hennekam (7), children with nMFS show severe probands with MFS diagnosed before1yoflife. In this population, mitral and/or tricuspid valvular insufficiency and infantile factors significantly associated with shorter survival are presence of pulmonary emphysema, in addition to the common symptoms valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26. (Pediatr Res 69: 265–270, 2011) of ectopia lentis, arachnodactyly, joint contractures, and loose skin. Death may occur within the first2yoflife from arfan syndrome (MFS) is an autosomal dominant con- congestive heart failure (7). Life expectancy seems to be the M nective tissue disorder (MIM 154700), the skeletal central issue when managing a patient with early diagnosed features of which were first described by Marfan (1) in 1896. MFS with cardiovascular involvement. To search for prognos- The cardinal features of MFS involve the cardiovascular, tic factors associated with early death, we studied the clinical ocular, and skeletal systems. The skin, lung, and dura may and molecular features of 60 probands carrying mutations in also be involved (2). The prevalence of MFS has been esti- the FBN1 gene and with cardiovascular involvement before mated at 2–3 per 10,000 of the population, and ϳ25% of cases the age of 1 y. are sporadic (3). Mutations in the gene encoding fibrillin-1, FBN1, are known to cause MFS and are widely distributed METHODS Patients. Patients were ascertained through the Universal Marfan database-FBN1 (UMD-FBN1; http://www.umd.be) (8), which collects molecular Received May 12, 2010; accepted October 14, 2010. data of patients carrying an FBN1 mutation from 38 countries in five Correspondence: Chantal Stheneur, M.D., Ph.D., Service de pe´diatrie, Hoˆpital A. Pare´, continents and registered between 1995 and 2008 and patients with a patho- 9, Avenue Charles de Gaulle, 92100 Boulogne, France; e-mail: chantal.stheneur@apr. genic FBN1 mutation unpublished were included (9,10). Inclusion criteria aphp.fr Supported by a Grant from the French Ministry of Health (PHRC 2004), GIS maladies rares 2004, Bourse de la Socie´te´ Française de Cardiologie, Fe´de´ration Française de Cardiologie 2005, Assistance Publique Hoˆpitaux de Paris (CIRC 2007), Abbreviations: IQR, interquartile ratio; MFS, Marfan syndrome; nMFS, and ANR-05-PCOD-014. neonatal MFS

265 266 STHENEUR ET AL. were as follows: i) clinical features allowing a diagnosis of MFS or type I fibrillinopathy in a child before the age of 1 y and ii) presence of cardiovascular manifestations including mitral and/or tricuspid valvular insufficiency and/or aortic root dilatation. These criteria were designed to exclude children with some skeletal features of the MFS spectrum but without cardiovascular involvement that could be diagnosed early based on a positive family history. They were also designed to exclude children with clinical features of MFS but mutated in an other gene such as TGFBR1 or TGFBR2 and to permit molecular description of the series. Sixty children diagnosed as MFS before the age of 1 y were identified, designated as nMFS or not by the clinician. Fifty-three of the probands were part of the 320 children described by Faivre et al. (11), whose study was designed for another purpose, and the remaining patients were issued from personal observations or recent publications. Informed consent has been obtained by each clinician. The required clinical information included a range of qualitative and quantitative clinical parameters, among them cardiovascular, ophthalmological, skeletal, skin, and lung manifestations. The age and cause of death or the age at last follow-up and the characteristics of FBN1 mutations were also collected. Patients still alive at last follow-up were designated as “survivors.” Statistical analysis. For descriptive purposes, time-to-event analysis tech- niques were used for survival analyses, and calculation of cumulative prob- ability of a clinical feature when the age at diagnosis was collected. Subjects for whom the age at diagnosis of a specific manifestation was not available were excluded from these analyses. Subjects who did not manifest the feature during the follow-up course were censored at their last follow-up. The baseline date (time zero) was the date of birth. In particular, the Kaplan-Meier method (12) was used to estimate the cumulative probabilities of clinical manifestations of the disease. To search for prognostic factors associated with shorter survival, comparison of prevalence of different clinical features was made between the group Figure 1. Kaplan-Meier analysis for survival in patients diagnosed as MFS of patients deceased before the age of 1 y and the group of patients alive at or type 1 fibrillinopathy before the age of 1 y. (A) Overall survival (solid line): this age. Only clinical features present before the age of 1 y were considered. 50% of patients were alive at 4 mo, IQR ϭ 2:66. Area between dashed lines Only patients with available follow-up beyond the age of 1 y were included show pointwise confidence bands (95%). (B) Survival in patients with a ␹2 in the analysis. The or Fisher exact test were used. mutation in FBN1 exons 25–26 (dashed line) vs patients with a mutation in Genotype-phenotype correlation analyses were difficult because of the other exons (solid line): 50% of patients with mutation within exons 25–26 small sample size. It was not possible to compare the type of mutations because the large majority of mutation was private missense mutations. We were alive at 3 mo, whereas 50% of patients with mutation located in other questioned whether the substitution of a cysteine residue was more likely to exons were alive at 12 mo. have phenotypic consequences than mutations affecting another amino acid. Because of the small sample size, it was not possible to compare the phenotypic data for each exon of the region with the others. Therefore, we insufficiencies. Notably, seven survivors (32%) have had a evaluated whether the phenotypic consequences of a mutation in the exons preferentially involved (exons 25 and 26) were different to the consequences valvular surgery. of mutations in the other exons. Differences among the different types of Clinical features of the overall study population are sum- mutation groups were tested using the nonparametric log-rank test. marized in Table 1. Ectopia lentis found in 24 of 52 patients We used SAS software version 9.2 (SAS Institute, Inc., Cary, NC) and Stata software version 9 (Stata Corp, College Station, TX) for all statistical (46%) was not always present at the time of diagnosis but analyses. The p values Ͻ0.05 were considered significant. The study has been evolved during follow-up in 11 of 24 patients. Spontaneous approved by the Assistance Publique Hoˆpitaux de Paris. pneumothorax was reported in five patients. Emphysema was recorded in two autopsy reports. Six patients had diaphrag- RESULTS matic hernia and all died in the first months of life (range, Clinical description of the population. Of the 60 probands, 0–3.5 mo). The presence of senile appearance, loose skin, and 58% (34/59) were males and 42% (25/59) were females. All crumpled ears that has been described as characteristic of cases were sporadic except for three siblings born to a father nMFS was noted in less than a third of patients. Dural ectasia with somatic and germline mosaicism (13). Therefore, 95% was checked only for five patients and was present in two. (57/60) of cases were de novo. Mean age at diagnosis was The most frequent cardiac manifestation was aortic root 0.05 Ϯ 0.2 y. dilatation (56/60, 93%), with a mean age at diagnosis of The median age at last follow-up was 4 mo [interquartile dilatation of 0.2 Ϯ 0.4 y (Fig. 2). Only two children (females) ratio (IQR), 2:66, extremes 0–26 y; Fig. 1]. Thirty-eight had aortic dissection, one child shortly after birth and another patients (63%) died during follow-up; among them 31 (82%) at the age of 12 y. In the study population, six probands (four before the age of 1 y and 34 (89%) before the age of 2 y. The males and two females) underwent aortic surgery during cause of death was congestive heart failure in 32 children infancy at a mean age of 5.4 Ϯ 6.4 y (range, 0.7–15 y). Two (85%), during or directly after cardiac surgery in three (8%), of them died after surgery at the age of 10 mo and 4 y, respiratory failure in two (5%), and in utero death in the respectively. The remaining patients were 2, 6, 20, and 26 y remaining patient. Among patients who died of congestive old, respectively, at last follow-up. heart failure, all had valvular insufficiencies. Among valvular insufficiencies, the most frequent was mi- The median age of the 22 survivors was 24 mo (IQR, 0:48). tral insufficiency in 81% of patients, with a mean age of 0.2 Ϯ They included 14 males and 8 females (NS). Among them, 21 0.4 y. Tricuspid insufficiency was found in 78% of patients (95%) had aortic root dilatation and 16 (73%) had valvular when mentioned. Aortic insufficiency was found in 40% of PROGNOSIS FACTORS IN MARFAN SYNDROME 267

Table 1. Frequency of skeletal, ocular, and cardiac phenotypes in study participants who died before the age of 1 y and those surviving at theageof1y(p values compare the two groups) Participants with available follow-up data All study participants Died before 1 y Surviving at 1 y p Pectus deformity 27/55 (49%) 11/29 (38%) 14/19 (74%) 0.02* Dolichostenomelia 20/44 (45%) 08/24 (33%) 10/16 (63%) 0.07* Arachnodactyly 57/57 (100%) 31/31 (100%) 20/20 (100%) NA Scoliosis 17/57 (30%) 05/31 (16%) 11/19 (58%) 0.02* Flexion contractures 47/54 (87%) 27/30 (90%) 16/19 (84%) 0.67† Pes planus 11/41 (73%) 04/24 (17%) 07/14 (50%) 0.06† Facial dysmorphism 50/57 (88%) 26/31 (84%) 18/19 (95%) 0.39† Joint hypermobility 36/54 (67%) 15/27 (56%) 15/20 (75%) 0.17* High-arched palate 35/46 (76%) 18/26 (69%) 14/16 (88%) 0.27† Ectopia lentis 24/52 (46%) 06/25 (24%) 09/21 (43%) 0.17* Ascending aortic dilatation 56/60 (93%) 28/31 (90%) 16/22 (73%) 0.14† Valvular insufﬁciencies 52/60 (87%) 29/31 (94%) 14/22 (64%) 0.01† Pneumothorax 05/56 (9%) 04/29 (14%) 01/20 (5%) 0.63† Diaphragmatic herniae 06/55 (11%) 06/28 (21%) 0/21 (0%) 0.03* * ␹2 test. † Fisher exact test. NA, not applicable.

are implemented in the new version of the UMD-LSDB software in the “UMD-Predictor” tool. Forty-seven different pathogenic FBN1 mutations were found (Table 2), seven of which were recurrent. There were 46 missense mutations (77%), nine splice-site mutations (15%), three inframe dele- tions or insertions (5%), and two frameshift mutations (3%). As no nonsense mutations were found, only two mutations led to a premature truncation of translation. Of the missense mutations, 63% involved a cysteine residue. Most mutations (98%) were located in an EGF domain, and only one was located in a TGFBP-like domain. Fifty-eight mutations (97%) were found in exons 24–32. One patient had a mutation in exon 4 (386GϾA) and one in exon 21 (2552_2566del; Table Figure 2. Percentage of different cardiac manifestations in probands during infancy. 2). Notably, 58% of mutations were clustered in exons 25 and 26 (Fig. 3). This overrepresentation of exons 25 and 26 was not found in other clinical manifestations (14). No compound patients, with a mean age of 0.1 Ϯ 0.5 y. Eight patients had heterozygosity was found. aortic dilatation without valvular involvement. Thirteen pa- We detected a significant difference for survival at 1 year tients (seven males and six females) had valvular surgery at a between patients carrying a mutation in exons 25–26 (27%; mean age of 1.7 Ϯ 1.5 y (range, 0.2 and 6 y). Among them, six 95% CI ϭ 13–44%) versus patients carrying a mutation died (46%) at a mean age of 2.2 Ϯ 2.1 y, including four elsewhere in the gene (48%; 95% CI ϭ 27–66%; Fig. 1B). patients shortly after surgery. The mean age at surgery was not Survival before 1 y was not significantly different in patients predictive of survival. Bicuspid aortic valve and congenital carrying a missense mutation involving a cysteine versus cardiomyopathy were each reported in three patients. Three another missense mutation. patients reached adulthood, two of them with multiple cardiac The two mutations leading to premature truncation are frame- and orthopedic surgeries. shift mutations located in exon 31 (3908_3909del) and 32 Comparison of probands who died before 1 year of age (4085_4091del; Table 2). The two patients had different surviv- and those who survived. The three features more frequently als. One patient died within the first year of life from congestive present in probands who died before1yofagewere aortic heart failure and the other was still alive at age 20 y after valvular dilatation (90 versus 73%, NS), valvular insufficiencies (94 and aortic surgeries. Similarly, among the two patients with a versus 64%, p ϭ 0.01), diaphragmatic herniae (21 versus 0%, mutation located outside of exons 24–32, one female died after p ϭ 0.03; Table 1). surgery for aortic dilatation at 4 y (exon 21) and one male was The deleterious effect of identified sequence variants was alive at 20 y and had not yet required surgery (exon 4). assessed by various algorithms [among which are Polymor- phism Phenotyping (PolyPhen); Sorting Intolerant From Tol- DISCUSSION erant (SIFT), Biochemical values, and BLOSUM 62], which were developed to predict whether a nucleotide variation is The goal of this study was to identify prognostic factors likely to affect protein function or not. All, except PolyPhen, associated with early death in a large population of genotyped 268 STHENEUR ET AL.

Table 2. Molecular characteristics of the 60 probands and their status at last follow-up Nomenclature Sex Status at last follow-up Exon Type of mutation 386GϾA M Alive at age 20 y 4 Missense involving a cysteine 2552_2566del F Died at age 4 y after cardiac surgery 21 Inframe deletion 3037GϾA F Alive at age 26 y 24 Missense IVS24 ϩ 5GϾT F Died in the first days of life of cardiac insufficiency 24 Splicing 3083AϾT M Died at 3 mo of life of cardiac insufficiency 25 Missense 3095GϾA F Died at 3 mo of life of cardiac insufficiency 25 Missense involving a cysteine 3095GϾA M Died within the first year of life of cardiac insufficiency 25 Missense involving a cysteine 3130TϾC F Alive in the first months of life 25 Missense involving a cysteine 3142_3144delATT M Died at 2 mo of life of cardiac insufficiency 25 Inframe deletion 3143TϾC M Died at 4 mo of life of cardiac insufficiency 25 Missense 3143TϾC F Died at age 5.5 y of sudden death 25 Missense 3143TϾC F Died at 3 mo of life of cardiac insufficiency 25 Missense 3143TϾC F Died at 2 mo of life of cardiac insufficiency 25 Missense 3143TϾC F Alive in the first months of life 25 Missense 3143TϾC F Died at 4 mo of life of cardiac insufficiency 25 Missense 3157TϾC F Died in the first days of life of cardiac insufficiency 25 Missense involving a cysteine 3157TϾC F Died at2yoflife of cardiac insufficiency 25 Missense involving a cysteine 3163TϾG F Died at 2 mo of life of cardiac insufficiency 25 Missense involving a cysteine 3165TϾG M Died in the first days of life of cardiac insufficiency 25 Missense involving a cysteine 3202TϾC F Alive in the first months of life 25 Missense involving a cysteine 3202TϾC; 3204CϾG F Died in the first months of life after cardiac surgery 25 Missense involving a cysteine 3202TϾG M Alive in the first months of life 25 Missense involving a cysteine 3209AϾG M Alive at 16 y of life 26 Missense 3215AϾG M Alive at age 2 y 26 Missense 3217GϾA M Died at3yoflife of cardiac insufficiency 26 Missense 3217GϾA F Died at 1 mo of life of cardiac insufficiency 26 Missense 3217GϾA M Alive in the first year of life 26 Missense 3217GϾAMIn utero fetal death 26 Missense 3220TϾC M Died at 2 mo of life of cardiac insufficiency 26 Missense involving a cysteine 3221GϾA M Died within the first year of life of cardiac insufficiency 26 Missense involving a cysteine 3241TϾG M Alive at age 2 y 26 Missense involving a cysteine 3256TϾC F Died at 1 mo of life of cardiac insufficiency and respiratory distress 26 Missense involving a cysteine 3256TϾC M Died in the first days of life of cardiac insufficiency 26 Missense involving a cysteine 3257GϾA M Alive in the first months of life 26 Missense involving a cysteine 3257GϾA M Died at 3 mo of life of cardiac insufficiency and respiratory distress 26 Missense involving a cysteine 3257GϾA M Died at 2 mo of life of respiratory distress 26 Missense involving a cysteine 3257GϾA M Died at 3 mo of life of respiratory distress 26 Missense involving a cysteine 3263AϾT M Died at1yoflife of cardiac insufficiency 26 Missense 3289TϾC F Alive in the first months of life 26 Missense involving a cysteine 3349TϾC M Alive at age 6 y 27 Missense involving a cysteine 3391AϾT F Died within the first months of life of cardiac insufficiency 27 Missense 3419GϾT M Died at 10 mo of life of cardiac insufficiency 27 Missense involving a cysteine 3458GϾC F Alive in the first months of life 27 Missense involving a cysteine 3545GϾC M Alive at age 3 y 28 Missense involving a cysteine 3602GϾA M Died in the first days of life of cardiac insufficiency 29 Missense involving a cysteine 3603_3668del Died at 3 mo of life of cardiac insufficiency 29 Inframe deletion 3667TϾC M Alive at age 4 y 29 Missense involving a cysteine 3706TϾC M Alive at age 4 y 29 Missense involving a cysteine IVS29 ϩ 1GϾC M Alive at age 1 y 29 Splicing IVS30 ϩ 1GϾA M Died at 4 mo of life of cardiac insufficiency 30 Splicing IVS30 ϩ 1GϾA M Died at 1 mo of life of cardiac insufficiency 30 Splicing IVS30 ϩ 3AϾT M Alive in the first year of life 30 Splicing 3901_3904del; M Alive at age 20 y 31 Frameshift 3908_3909del IVS30-1GϾT F Died within the first months of life of cardiac insufficiency 31 Splicing IVS31 ϩ 1GϾA F Died at 5 mo of life of cardiac insufficiency 31 Splicing 3976TϾC F Alive at age 3 y 32 Missense involving a cysteine 4009GϾC F Alive at age 1 y 32 Missense 4085-4091del M Died at1yoflife of cardiac insufficiency 32 Frameshift IVS31-2AϾT F Died at 3 mo of life of cardiac insufficiency 32 Splicing IVS31-2AϾG M Died at 4 mo of life of cardiac insufficiency 32 Splicing patients diagnosed with MFS or type I fibrillinopathy before 1 in an FBN1 for two reasons. First, to avoid overlapping year of age gathered through an international collaboration. phenotypes, e.g. Beals syndrome associated with an FBN2 We chose to include only those probands carrying a mutation gene mutation (15), MFS type 2 and Loeys-Dietz syndrome PROGNOSIS FACTORS IN MARFAN SYNDROME 269 distribution of mutations differ from those described in the general MFS population (20,21). We confirmed that the hot spot region for MFS diagnosed before 1 y of age is located between exons 24 and 32; however, we newly discovered that exons 25 and 26 are most often involved (58% of mutations) whatever clinical presentation. Because two mutations were found outside the exons 24–32 region, it remains justifiable to sequence the whole FBN1 gene when no mutation is found in a first-step analysis of exons 24–32. Only two mutations leading to premature truncation were found and there were no nonsense mutations. These results are in agreement with previous results from Faivre et al. in patients mutated in exons Figure 3. Percentage of mutations in the “exon 24–32 region” when compared with the percentage of mutations found in other MFS phenotypes: for 24–32 whatever the severity of the disease (nMFS, severe each exon, black bars represent the percentage of patients diagnosed as MFS MFS, classical MFS, probable MFS, or other type I fibrilli- before the age of 1 year (n ϭ 60) and white bars the percentage of mutations nopathy). Indeed, the authors showed that premature truncated found whatever the phenotype (n ϭ 155). **p Ͻ 0.0001 and *p ϭ 0.002. codons (PTCs) were underrepresented in patients with severe phenotypes with an absence of nonsense mutations, whereas linked to TGFBR1 or 2 gene mutations (16–18), and second, missense mutations were overrepresented. It is not known to allow for description of the molecular characteristics and whether this could be explained by early lethality or by a search for genotype-phenotype correlations. We chose to milder phenotypic effect of mutations leading to premature avoid the term of neonatal MFS because the dividing line truncations within the exon 24–32 region. Few data are between neonatal MFS and severe infantile MFS is difficult to available to assess the true effect of mutations leading to define. In an editorial, Hennekam (7) proposed that the term premature truncations and whether they are subjected to non- nMFS should be restricted to neonates who show severe mitral sense-mediated RNA decay or give rise to truncated peptides and/or tricuspid valvular insufficiency and infantile pulmonary of various sizes (22). The difference in clinical manifestation emphysema. The presence or absence of pulmonary emphy- between both patients with truncating mutations could be sema was rarely ascertained in our series; therefore, we could explained by a different pathogenesis, dominant negative ef- not apply this definition. Although rare events, two cases who fect versus nonsense-mediated decay. Until more information died before1yofagefrom respiratory distress did not have is available, the true impact on microfibril formation from valvular insufficiency. The presence of ascending aortic dila- mutations leading to premature truncations remains specula- tation was not part of the definition of nMFS; however, in our tive. In their study, Schrijver et al. (23) found that the position series, it was as common as valvular insufficiency, especially of a substituted cysteine residue within an EGF-like domain of in patients who died before1yofage. Nevertheless, the fibrillin 1 has an effect on the severity of symptoms in MFS. presence or absence of ascending aortic dilatation was not In our population, we have compared the mutation position in predictive of early death. A significant result was only found probands who died before the age of 1 y and those alive after for the presence of valvular insufficiencies and diaphragmatic this age, but we could not find any significant difference, hernia, indicating that both features could be considered as probably because of the size of our sample. adverse prognostic criteria. Morse et al., (19) reported their In conclusion, we report the largest genotyped series of own series of 22 patients severely affected infants diagnosed probands with MFS diagnosed before1yoflife. We found with MFS in the first 3 mo of life, together with a review of that the presence of valvular insufficiencies and diaphragmatic 32 additional infants described in the literature. 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